CAPT Alicia M. Mozzachio, RPh, MPH Branch Chief, International Compliance Branch

Office of Manufacturing & Product Quality Office of Compliance, CDER, FDA

Post-Approval & Surveillance Inspection Programs for Pharmaceutical Manufacturers

Agenda

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Organizational Overview – Office of Manufacturing & Product Quality

Roles and Responsibilities

GDUFA and You (related to inspections)

FDA Inspection Types and Techniques

Hosting an Inspection

Before, during, and after

Dos and Don’ts

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Michael Smedley Deputy Director

Steven Lynn Office Director

Kennerly Chapman (Actg) Associate Director for

Program Management & Org Strategy

Brian Hasselbalch (Actg) Associate Director for

Policy & Communication

Vacant Associate Director for

Regulatory Science

Carmelo Rosa Div. Director

Division of International Drug Quality

David Doleski Div. Director

Division of Good Manufacturing Practice

Assessment

Brian Hasselbalch (Actg) Division of Policy,

Collaboration & Data Operations

Teddi Lopez Div. Director

Division of Domestic Drug Quality

Policy & Guidance Team

Collaboration & Leveraging Team

Alicia Mozzachio

Branch Chief Int’l Compliance Branch 1

Rosa Motta Branch Chief

Domestic Compliance Branch 1

Coki Cruz

Branch Chief Int’l Compliance Branch 2

Milind Ganjawala (Actg)

Branch Chief Domestic Compliance

Branch 2

Elise Murphy Branch Chief

Drug Surveillance & Data Reporting Branch

Zhihao (Peter) Qiu Branch Chief

Biotech Manufacturing Assessment Branch

Francis Godwin (Actg) Branch Chief

Generic Drug Manufacturing Assessment

Mahesh Ramanadham (Actg) Branch Chief

New Drug Manufacturing Assessment Branch

Rick Friedman Associate Director for Risk

Science, Intelligence & Prioritization

Paula Katz (Actg) Branch Chief

Regulatory Policy & Collaboration Branch

Office of Manufacturing and Product Quality 3

OMPQ Roles & Responsibilities

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Office of Manufacturing and Product Quality (OMPQ) reviews and approves CGMP regulatory actions based on scientific and technical merit

OMPQ acts as a liaison between the field and Center offices to evaluate and coordinate product quality issues and to determine if regulatory action is necessary

Participate in establishment inspections – both foreign and domestic

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Generic Drug Program: Not just OGD •

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Involves all of CDER OGD is the interface for ANDA applicants to interact with the Generic Drug Program

Other FDA units: ORA (the field) CDRH Office of the Commissioner Office of Chief Counsel

OGD

Office of Compliance Office of

Pharmaceutical Science

Office of New Drug

Office of Surveillance

and Epidemiology

Office of Translational

Sciences

Others Office of Medical Policy

Office of Communications

Office of Strategic Planning

Office of Management

Office of Executive Programs

Office of Counter-

Terrorism and Emergency

Coordination

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Key Aims of GDUFA

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Safety – Ensure that industry participants are held to high quality standards & are inspected biennially w/ foreign & domestic parity.

Access – Expedite the availability of low cost, high quality generic drugs by bringing greater predictability to the review process.

Transparency - Requiring the identification of facilities involved in the manufacture of generic drugs and improving FDA’s communications and feedback with industry in order to expedite product access.

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FDA Inspection Commitments: •

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Prioritize establishment inspections ANDAs that are otherwise approvable or eligible for tentative approval except for an outstanding inspection and establishments not inspected previously

Public Information: results and date of inspection Make inspection classification results and date of the last facility inspection available to the public and industry on FDA’s website

Foreign inspections Study foreign government regulator inspections, report findings publicly, and develop a program to utilize foreign inspections classifications when and where appropriate

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Which facilities routinely get inspected?

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dosage form active pharmaceutical ingredient excipient clinical trial material “biotech” (e.g., MaB; therapeutic proteins) medical gas processors and transfillers contract packagers/labelers contract sterilizers contract laboratories ‘export-only’ involved in any of above

? ?

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1903 General Inspection Protocol ••

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The visit of the inspectors shall be unannounced It shall be the duty of the inspectors to call first upon the head of the establishment or member of the firm, stating the object of their visit. The proprietor of the establishment being inspected shall extend every facility to the inspectors to aid them in their work. The inspectors shall be permitted to examine all portions of the premises, appliances, methods, stables, barns, warehouses, records, and, if requested by the inspectors, shall be shown the methods employed in actual operation. The inspectors are authorized, when they consider it necessary, to interrogate the proprietor, members of the firm, and employees of the establishment under oath.

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2013 General Inspection Protocol

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Arrive unannounced Ask for the most responsible person

show credentials (i.e., special photo ID) issue a written “Notice of Inspection” (FDA 482) briefly state objective of the inspection

Conduct inspection (facility/records/people) issue written “Inspectional Observations” (FDA 483) when warranted collect samples, as needed (FDA 484) take affidavits, as needed

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Post-Approval Inspections

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Surveillance (Routine) CGMP Inspections comprehensive; risk-based frequency

For-Cause (Compliance) Inspections directed; usually very specific purpose

f/u past violations f/u on complaint, informant allegation

“Post-Approval” product specific soon after approval

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Human Drug CGMP Compliance Programs •••••••

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7356.002: Drug Manufacturing Inspections 7356.002A: Sterile Drug Process Inspections 7356.002B: Drug Repackagers & Relabelers 7356.002C: Radiopharmaceuticals 7356.002E: Medical Gases 7356.002F: API Process Inspection 7356.002M: Inspections of Licensed Biological Therapeutic Drug Products 7356.002P: Positron Emission Tomography 7356.843: Post-Approval Inspections 7346.832: Pre-approval Inspections (A-NDA/BLA)

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm252671.htm

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What is covered during a routine CGMP inspection?

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Goals of Routine CGMP Inspections: 7356.002

Determine compliance with CGMP requirements; provide evidence for action as necessary

Support application approval decisions

Provide feedback to firms to improve their compliance; and,

Aid FDA in determining the adequacy of CGMP requirements, regulatory policy, and guidance

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Systems-based Inspections

1. Quality System

2. Facilities and Equipment System

3. Materials System

4. Production System

5. Packaging and Labeling System

6. Laboratory Control System

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How is a System covered? •

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Sufficiently detailed, with specific examples to determine state of control for every profile class

profile class = categorization of different processing conditions & product types

related to requirements (CGMPs)

If System is in control, all profiles covered by system are deemed in control

Unique profile class material/process under a system selected at discretion of Investigator

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Inspection Rigor

1. Full Inspection Option

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Quality System + NLT 3 other systems

2. Abbreviated Inspection Option

Quality System + NLT 1 other system

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Inspection Rigor

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Full Inspection When:

initial establishment inspection

previous inspection findings warrant; violative history

significant changes since last inspection

Abbreviated Inspection Permitted If:

good history

no major changes to operations

no pattern of recalls and problems 18

Why a ‘Systems’ Approach?

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Reinforces proactive compliance & reduces reliance on FDA as QA

Extrapolation: judgment made on all products based on Systems & products actually inspected

Potentially decreased time to inspect, overall

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“Post-Approval” Inspection

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Product-specific; soon following application approval

Assigned/requested; carefully selected

Covers aspects of Quality...

1. not ready during application review period, and

2. more critical to assure quality

Including: process validation component supplier qualification stability

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Manufacturer’s Role: Before

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Register facility and list all drugs

If associated with an application keep DMF current; aligned with application role

be ready to justify any changes since approval

Know and follow the quality regulations and guidance

Be confident in your staff and your operation cultivate honesty and integrity

be able to explain why you do what you do

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Manufacturer’s Role: During

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Allow access to all areas of manufacturing facility, equipment, materials, records, people

Answer questions don’t answer if unsure; check

Provide all info requested clarify request if unclear indicate how long it will take can redact financial info

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Manufacturer’s Role: After •

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Inspectional Observations not issued expect a copy of FDA inspection report reinspection from 2 – 4 years depending on facility and FDA’s risk model

Inspectional Observations issued the 483 is for you; ask questions if unclear inform investigator of any incorrect statements if citation isn’t scientifically valid, explain why and…

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Manufacturer’s Role: After Got a 483?

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Do… correct ASAP if you agree assess hazard w/ marketed batches respond in writing within 15 days be very specific with what and when attach copies explain why an observation isn’t significant or is incorrect

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Manufacturer’s Role: After Got a 483?

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Don’t… make excuses promise what you can’t deliver ignore the bigger picture be afraid to disagree

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Enforcement of Quality Standards (CGMPs)

1. Inspection findings are reviewed in District–––

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written warning of violations withhold/withdrawal marketing approval seizure/injunction/criminal prosecution

2. FDA CDER Office of Compliance reviewsrecommendation + firm’s response to 483

accept or reject or alter action shortage evaluation advisory/administrative actions taken (warnings, import alerts, application withhold)

3. FDA/OCC reviews seizure/injunction/prosecution4. DOJ + FDA/OCC litigates

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Frequently-Observed Quality Problems and CGMP Violations

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Investigating & correcting discrepancies or defects (211.192)

Micro controls for sterile & non-sterile (211.113)

Stability program (211.166(a))

Process design & qualification (validation) (211.100(a))

Establishing & following sound tests & sampling plans (211.160)

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Where to Get Help with CGMPs and Quality Issues

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm096102.htm

http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/default.htm

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Acknowledgements

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Brian Hasselbalch

Thomas Hinchliffe

Paula Katz

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